Eight viruses have been identified which are members of the family Herpesviridae (reviewed in Roizman, B. 1996. Herpesviridae, p. 2221–2230. In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.). Each member of this family is characterized by an enveloped virus containing a proteinaceous segment and nucleocapsid, the latter of which houses the viruses' relatively large double-stranded DNA genome (i.e. approximately 80–250 kilobases). Members of the human alpha-herpes-virus subfamily are neurotropic and include herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), and varicella-zoster virus (VZV). The human beta-herpes-viruses are cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7). The gamma-herpes-viruses are lymphotropic and include Epstein-Barr virus (EBV) and Kaposi's herpes-virus (HHV-8). Each of these herpes-viruses is causally related to human disease, including herpes labialis and herpes genitalis (HSV-1 and HSV-2), [Whitley, R. J. 1996, Herpes Simplex Viruses, p. 2297–2342, in B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]; chicken pox and shingles VZV), [Arvin, A. 1996. Varicella-Zoster Virus, p. 2547–2585, In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed, Lippincott-Raven Publishers, Philadelphia, Pa.]; infectious mononucleosis (EBV), [Rickinson, A. B. and Kieff, E. 1996, Epstein-Barr Virus, p. 2397–2446, In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed, Lippincott-Raven Publishers, Philadelphia, Pa.]; pneumonia and retinitis (HCMV), [Britt, W. J., and Alford, C. A. 1996, Cytomegalovirus, p. 2493–2523, In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed, Lippincott-Raven Publishers, Philadelphia, Pa.]; exanthem subitum (HHV-6), [Pellet, P. E, and Black, J. B. 1996, Human Herpes-virus 6, p. 2587–2608, In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.] and (HHV-7), [Frenkel, N., and Roffman, E. 1996, Human Herpes-virus 7, p. 2609–2622, In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]; and Kaposi's sarcoma (HHV-8), [Neipel, F., Albrecht, J. C., and Fleckenstein, B. 1997, Cell-homologous genes in the Kaposi's sarcoma-associated rhadinovirus human herpes-virus 8: determinants of its pathogenicity? J. Virol. 71:4187–92,1997]. HCMV is considered in more detail below. Following the primary infection, herpes-viruses establish latency within the infected individual and remain there for the remainder of his/her life. Periodic reactivation of latent virus is clinically relevant. In the case of HSV, reactivated virus can be transmitted to infants during birth, causing either skin or eye infection, central nervous system infection, or disseminated infection (i.e. multiple organs or systems). Shingles is the clinical manifestation of VZV reactivation. Treatment of HSV and VZV is generally with antiviral drugs such as acyclovir (Glaxo Wellcome), ganciclovir (Roche) and foscarnet (Asta) which target viral encoded DNA polymerase.
HCMV is a ubiquitous opportunistic pathogen infecting 50–90% of the adult population [Britt, W. J., and Alford, C. A. 1996, Cytomegalovirus, p. 2493–2523, In B. N. Fields, D. M. Knipe, and P. M. Howley (ed.), Fields Virology, 3rd ed. Lippincott-Raven Publishers, Philadelphia, Pa.]. Primary infection with HCMV is usually asymptomatic, although heterophile negative mononucleosis has been observed. The virus is horizontally transmitted by sexual contact, breast milk, and saliva. Intrauterine transmission of HCMV from the pregnant mother to the fetus occurs and is often the cause of serious clinical consequences. HCMV remains in a latent state within the infected person for the remainder of his/her life. Cell-mediated immunity plays a central role in controlling reactivation from latency. Impaired cellular immunity leads to reactivation of latent HCMV in seropositive persons.
HCMV disease is associated with deficient or immature cellular immunity. There are 3 major categories of persons with HCMV disease (reviewed by Britt and Alford, 1996). (1) In immunocompromised (AIDS) patients, HCMV is one of the two most common pathogens causing clinical disease (the other is Pneumocystis). The most common manifestation of HCMV in AIDS is retinitis, although infection of other organs including the adrenal glands, lungs, GI tract, and central nervous system are also reported frequently. 90% of AIDS patients have active HCMV infection; 25–40% (˜85,000 patients in the United States) have life- or sight-threatening HCMV disease. HCMV is the cause of death in 10% of persons with AIDS. (2) Due to immune system suppression to reduce the risk of graft rejection, HCMV reactivation or reinfection is common amongst kidney, liver, heart, and allogeneic bone marrow transplant patients. Pneumonia is the most common HCMV disease in these patients, occurring in up to 70% of these transplant patients. (3) Congenital infection due to HCMV occurs in 1% of all births, about 40K per year. Up to 25% of these infants are symptomatic for HCMV disease between ages 0–3 years. HCMV disease is progressive, causing mental retardation and neurological abnormalities in children. Recent studies suggest that treatment with anti-HCMV drugs may reduce morbidity in these children.
Several antiviral drugs are currently being marketed [D. Bron, R. Snoeck, and L. Lagneaux 1996, New insights into the pathogenesis and treatment of cytomegalovirus, Exp. Opin. Invest. Drugs 5:337–344; Crumpacker, C. 1996, Ganciclovir, New Eng. J. Med. 335:721–729; Sachs, S., and F. Alrabiah, 1996, Novel herpes treatments: a review. Exp. Opin. Invest. Drugs 5:169–183]. These include: ganciclovir (Roche), a nucleoside analog with hemopoietic cell toxicity; foscarnet (Astra), a pyrophosphate analog with nephrotoxicity; and cidofovir; (Gilead), a nucleoside phosphonate with acute nephrotoxicity. Each of these drugs target the viral-encoded DNA polymerase, are typically administered intravenously due to their low bioavailability, and, as noted above, are the source of significant toxicity. Ganciclovir-resistant mutants which arise clinically are often cross-resistant with cidofovir. Hence, there is a need for safer (i.e. less toxic), orally bioavailable anti-viral drugs which are directed against novel viral targets.
Phenyl thioureas are disclosed for use in a variety of pharmaceutical applications. Armistead, et al., WO 97/40028, teaches phenyl ureas and thioureas as inhibitors of the inosine monophosphate dehydrogenase (IMPDH) enzyme which is thought to play a role in viral replication diseases such as herpes.
Widdowson, et al., WO 96/25157, teaches phenyl urea and thiourea compounds of the below formula for treating diseases mediated by the chemokine, interleukin-8.
Morin, Jr., et al., U.S. Pat. No. 5,593,993 teaches certain phenyl thiourea compounds for treatment of AIDS and the inhibition of the replication of HIV and related viruses.
The compounds of this invention are potent structurally unique VZV inhibitors.